Substituted benzofurans

ABSTRACT

The compounds of this invention are substituted benzofurans having pharmacological activity. In particular, these compounds have coronary vasodilator activity and are useful in the treatment of angina pectoris.

United States Patent Hill et al.

[111 3,880,891 451 Apr. 29, 1975 SUBSTITUTED BENZOFURANS Inventors:David T. Hill, North Wales; Bernard Loev, Broomall, both of Pa.

SmithKline Corporation, Philadelphia. Pa.

Filed: Sept. 21, 1973 Appl. No.: 399,573

Assignee:

US. Cl 260/346.2 R; 260/247.2 B; 260/247.5 R; 260/247.7 A; 260/293.58;260/326 A; 260/326.34; 260/326.5 D; 424/248;

Int. Cl C07d 5/42 Field of Search 260/346.2 R. 247.2 E.

260/247.7 A, 247.5 R, 293.58, 326.5 D, 326.34, 326 A [56] ReferencesCited UNITED STATES PATENTS 3,248,40l 4/l966 Tondcur et al. 260/346.2

Primary E.\'aminer-Henry R. .liles Assistant E.\'aminerBernard l. DentzV Attorney, Agent, or Firm-Joan S. Keps; Richard D. Foggio; William H.Edgerton 8 Claims, No Drawings SUBSTITUTED BENZOFURANS Thisinventionrelate to new substituted benzofurans which have usefulpharmacological activity. More specifically, the compounds of thisinvention have coronary vasodilator activity and are useful in thetreatment of angina pectoris. In addition, these compounds may be usefulas hypotensive agents.

The compounds of this invention are represented by the followingstructural formula:

FORMULA I or a pharmaceutically acceptable acid addition salt thereof,in which:

R, is hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl; Ris hydrogen, lower alkyl or phenyl (Cl-l where n is O or 1 and thephenyl moiety is optionally substituted with lower alkyl, lower alkoxy,trifluoromethyl, halogen, NH NH(lower alkyl) or N(lower R is hydrogen,halogen, lower alkyl or lower alkoxy;

m is l or 2;

R R and R are hydrogen or one of R R and R is methyl or ethyl;

R5, is hydrogen or lower alkanoyl; and

R is NH(lower alkyl), N(lower alkyl) NH(benzyl),

N(lower alkanoyl)(lower alkyl), piperidino, pyrrolidino, morpholino orsuccinimido.

As used herein, the terms lower alkyl and lower alkoxy denote groupshaving from one to four carbon atoms and lower alkanoyl denotes groupshaving from two to four carbon atoms.

Preferred compounds of this invention are repre sented by Formula I inwhich R is hydrogen, lower i c l Formula II alkyl or phenyl(CH where nis O or 1 and the phenyl moiety is optionally substituted with methyl,methoxy, trifluoromethyl or chloro, R R and R are hydrogen, R ishydrogen or methyl and R is NH(isopropyl) or NH(t-butyl). Most preferredare those compounds in which R, is hydrogen or chloro in the 5-position,R is hydrogen, lower alkyl or phenyl(CH where n is 0 or 1 and the phenylmoiety is optionally substituted with methyl, methoxy, trifluoromethylor chloro, R is hydrogen or halogen, m is l R R R and R are hydrogen andR is NH(isopropyl) or NH(t-butyl).

Advantageous compounds of this invention are rep- (IJH 0-CH -CH-CH -R a,or-

R is hydrogen or chloro, m is l and R is NH(isopropyl) or NH(t-butyl).

Particularly preferred are the compounds Z-n-butyl-3-[4'-(2-hydroxy-3isopropylamino)propoxybenzoyl]- benzofuran,2-n-butyl-3-[3'-chloro-4-(2-hydroxy-3-isopropylamino)-propoxybenzoyl]benzofuran, 2-nbutyl-3-[4'-chloro-2'(2-hydroxy-3- isopropylamino)propoxybenzoyl]benzofuran and 2-(4'-chlorobenzyl)-3-[4 2-hydroxy-3-isopropylamino)-propoxybenzoyllbenzofuran.

The compounds of this invention may exist as optical isomers due to theasymmetric carbon atom in the side chain of the acyl group: All of theisomers, including separated isomers and "'rnixtures thereof, areincluded within the scope of this invention.

The compounds of Formula I in which R is hydrogen and R is NH(loweralkyl), N(lower alkyl) NH(benzyl), piperidino, pyrrolidino, morpholinoor succinimido are prepared as shown in the following scheme:

scum 1 0 fa R R ii ti it 7 SCHEME I Continued Fqrmula III v R H Theterms R R R R R R and m are defined as above and R is NI-I(lower alkyl),N(lower alkyl) NI-I(benzyl), piperidino, pyrrolidino, morpholino orsuccinimido.

Accroding to the above procedure, a hydroxyphenyl benzofuranyl ketone ofFormula II is converted to the epoxy intermediate III which is thenopened by reaction with an appropriate amine (R /H). When R R and R arehydrogen, the epoxy intermediates of Formula III are prepared byreaction of a compound of Formula II with an epihalohydrin such asepichlorohydrin or epibromohydrin in the presence of a base such assodium hydroxide or potassium carbonate in a solvent such as water,ethanolor acetone. When one of R R and R is methyl or ehtyl, thecorresponding compounds of Formula Ill are prepared by reaction of ahydroxyphenyl benzofuranyl ketone with a chloroalkene to give analkenyloxyphenyl benzofuranyl ketone which is then epoxidized withm-chloroperbenzoic acid.

' The ring opening of the epoxy intermediates of Formula Ill ispreferably carried out in a minimum amount of a solvent such as ethanolor with excess amine as solvent in Parr pressure bomb at from about toabout 150C. for from 1 to about 48 hours.

The product propanolamines are isolated and purifled as such-.by,standard techniques including solvent extraction, crystallization andchromatograhic methods or as the corresponding acid addition salts whichare formed with organic and inorganic acids according to methods knownto the art. Thus,-a solution of the amine in ether or an alcohol such asmethanol or ethanol is treated with a solution of an organic orinorganic acid in an aqueous miscible solvent, such as acetone orethanol, with isolation of the salt by concentration and cooling or inan aqueous immiscible solvent, such as ether or chloroform, with thedesired salt separating directly. Exemplary of such organic salts arethose with maleic, fumaric, benzoic, ascorbic, pamoic, succinic,

hexamic, oxalic, bismethylenesalicylic, methanesulglycolic,p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acidsas well as with the 8- halotheophyllines, for example,8-bromotheophylline. Exemplary of such inorganic salts are those withhydrochloric, hydrobfomic, sulfuric, 'sulfa'mic, phosphoric and nitricacids. Of course, these salts ma'y'also be prepared by the classicalmethod of double decomposition of appropriate salts which is well knownto the art, The salts may be purified by the standard methods describedabove.

Also formed in the reaction of II with epichlorohydrin is a compound ofFormula IV:

Formula IV The ratio of III and IV is variable and depends on the natureof R R and R m, their relative positions and the base employed in thereaction. III and IV are sepa rated by standard wet or dry columnchromatographic methods. The compounds of Formula IV may be converted tothe corresponding epoxy intermediates of Formula III by stirring asolution of IV in aqueous dioxane containing a base such as sodiumhydroxide for from 1 to about 12 hours at about 25 to about C; or may bereacted with an amine as previously described to give the correpsondingcompounds of For mula I directly.

The hydroxyphenyl benzofuranyl ketone starting materials of Scheme I, inwhich R is in the 2-position and R is in the 3-position of thebenzofuran nucleus (V) are either known to the art or are prepared asoutlined below:

SCHEME II 0 OH R OCH HO- Cl-C l) SnCl 2) Demethylation OH Ii m R FormulaV According to Scheme 11, a hydroxybenzoic acid is methylated bystandard methods, for example with dimethyl sulfate, converted to thecorresponding acid chloride with thionyl chloride and subsequently usedto acylate a benzofuran nucleus by standard procedures, for example inthe presence of stannic chloride in a solvent such as methylene chlorideor carbon disulfide. The methoxyphenyl benzofuranyl ketones aredemethylated by known methods, for example by use of pyridinehydrochloride or boron tribromide. These and other methods are describedby Buu-l-loi et al., J. Chem. Soc. 3693 (1955), 625 (1957), 2593 (1957),173 (1964) and in Japanese Pat. No. 2482/64.

Alternatively, the hydroxyphenyl benzofuranyl ketone starting materialsare prepared by addition of a methoxyphenyl magnesium halide to a 3-cyanobenzofuran followed by hydrolysis and subsequent demethylation aspreviously described.

The benzofuran nuclei used as starting materials in Scheme 11 are eitherknown to the art or are prepared by one of the general methods for thesynthesis of benzofurans described by Buu-l-loi et al.,supra, Tanaka, J.Amer. Chem. Soc. 732872 (1951), Bisagni et al., J. Chem. Soc. 3688(1955), Grinev et al., Zhur. Obshchei Khim. 27:1087 (1957) and Castro etal., J. Org. Chem. 28:3313 (1963), 3124071 (1966), in Rodd, Chemistry ofCarbon Compounds V01. IV-A, 168191 and in French Patent 1,537,206.

To prepare the compounds of Formula I in which R; is in the 3-positionand R is in the 2-position of the benzofuran nucleus, the requiredhydroxyphenyl benzofuranyl ketone starting materials of Scheme 1 areeither known to the art or are prepared by the method of Buu-Hoi et al.,J. Chem. Soc. 3693 (1955) and 2593 a? (1957) shown in Scheme lll:

SCHEME III i OCH BrCH I 1) Base 2) Demethylation Formula VI Reaction ofa salicylic acid or an o-hydroxyphenyl ketone with a substituteda-bromoacetophenone in the presence of base followed by demethylation asdescribed above gives the hydroxyphenyl benzofuranyl ketones of FormulaV1.

The compounds of Formula I in which R, is bromine, m is 2, R is hydrogenand R is R as defined above may also be prepared by treatment of thecorresponding hydroxyphenyl benzofuranyl ketoneswhere R is hydrogen withbromine in acetic acid followed by epoxide formation and subsequent ringopening with R H. Similarly, treatment of the hydroxyphenyl benzofuranylketones where R, is hydrogen with N- bromosuccinimide indimethylformamide gives the compounds of Formula II where R is bromo andm is 1. When R is chloro and m is 2, the compounds of Formula 11 may bealternatively prepared from reaction of the hydroxyphenylbenzofuranylketones where R, is hydrogen with potassium hypochlorite inmethanol and aqueous base.

The compounds of this invention in which R is lower alkanoyl and R isN(lower alkanoyl)(lower alkyl) are prepared from the correspondingcompounds of Formula I where R is hydrogen and R is NH(lower alkyl) byconventional methods, for example, by reaction of the hydroxy compoundwith a lower alkanoic acid anhydride or a lower alkanoyl halide, Alsoformed in this reaction are the corresponding compounds of Formula 1 inwhich R is lower alkanoyl and R is NH(lower alkyl). These products areseparated by standard chromatographic methods. When R is hydrogen and Ris N(lower a1kyl) piperidino, pyrrolidino, morpholino or succinimido,treatment with lower alkanoic acid anhydride or a lower alkanoyl halideyields the corresponding compounds of Formula I in which R is loweralkanoyl. Basic hydrolysis of the N,O-di-(lower alkanoyl) compounds ofthis invention give the corresponding compounds of Formula 1 in which Ris hydrogen and R is N(lower a1kanoyl)(lower alkyl).

The coronary vasodilator activity and hypotensive effects of thecompounds represented by Formula I are demonstrated in dogs by anincrease in coronary blood flow with concomitant decrease of meanarterial blood pressure upon intravenous administration of doses of fromabout 0.5 to about 5.0 mg./kg. These parameters are measured as follows:

Adult mongrel dogs (13-16 kg.) are pretreated with 2 mg./kg. so ormorphine sulfate followed in one hour by intravenous administration of1-1.5 mL/kg. of an aqueous solution containing 1.5 percent chloraloseand 20 percent urethane. Supplemental doses of morphine andchloralose-urethane are given to maintain an adequate and uniform depthof anesthesia.

A carotid artery is catheterized and connected to a Sanborn pressuretransducer to measure arterial blood pressure. A femoral vein is alsocatheterized for administering a solution of the test compound or itssalt and supplemental anesthesia. A left thoractomy is made at thefourth or fifth intercostal space, the lung is displaced, thepericardium is opened and the left circumflex coronary artery isisolated for measurement of coronary blood flow, a snare being placedaround the artery distally to obtain zero flow. Coronary blood flow ismeasured with a Statham electromagnetic flowmeter and Flo-Probe (MDS).

In addition, many of the compounds of this invention,

for example those represented by Formula I in which R is hydrogen, R isR is hydrogen or methyl and R is NH(lower alkyl), N(lower alkyl) orNH(benzyl) also inhibit or attenuate the chronotropic effect ofisoproterenol-induced tachycardia upon administration to dogs at dosesof from about 0.63 to about 5.0 mg.kg. i.v. Abad et a1. [Acta Pharmacol.et Toxicol. 25:85 (1967)] have correlated the inhibition ofisoproterenol-induced tachycardia to utility as an anti-anginal agent.

One skilled in the art will recognize that in determining the amounts ofthe compound needed to produce the desired pharmacological effectwithout toxic side effects, the activity of the compound as well as thesize of the host animal must be considered.

The following examples illustrate the invention but are not to beconstrued as limiting the scope thereof. Temperatures are in degreesCentigrade unlses otherwise stated.

When formed, acid addition salts may be converted to the correspondingfree amines by treating a solution of the salt in water, achloroform-water or a benzenewater mixture with 10 percent aqueoussodium hydroxide, sodium carbonate or sodium bicarbonate until basicfollowed by extraction of the amine into benzene or chloroform. Saltsother than hydrochlorides may be converted to the correspondinghydrochloric acid salts by passing a solution of the salt in methanol orethanol through an Amberlite IRA-401 chloride ion exchange column.

EXAMPLE 1 2-n-Butyl-3-[4 2-hydroxy-3- isoproylamino )propoxybenzoyl-benzofuran To a solution of 8.7 g. (0.03 mol.) of 2-n-butyl-3-(4'-hydroxybenzoyl)benzofuran in 100 ml. of water containing 1.4 g. (0.035mol.) of sodium hydroxide was added dropwise 4.0 g. (0.044 mol.) ofepichlorohydrin. The reaction mixture was stirred and refluxed for 1hour, then cooled and extracted with chloroform. The extracts werewashed with water and a saturated aqueous solution of sodium chloride,dried (MgSO and concentrated to yield a mixture of 2-n-butyl-3-[4-(2,3-epoxy)propoxybenzoyl]benzofuran and 2-n-butyl-3-[4'-(2-hydroxy-3-chloro)propoxybenzoyl]-benzofuran which was separatedby dry column chromatography on alumina with chloroform as the eluant.

The chlorohydrin product was dissolved in 10 percent aqueous dioxanecontaining an excess of one molar equivalent of sodium hydroxide andstirred at 25 for 2 hours to effect conversion to the epoxide, m.p.6l62.

A solutin of 1.5 g. (0.004 mol.) of 2-n-butyl-3-[4'-(2,3-epoxy)propoxybenzoyl]benzofuran and 25 ml. of isopropylamine in ml.of ethanol was heated in a Parr pressure bomb for 12 hours at 120. Aftercooling,

the solvent and excess amine were removed in vacuo to give the titlecompound which was dissolved in ether and treated with an etherealsolution of hydrogen chloride until pH 2-4. The precipitated salt wascollected and recrystallized from isopropanol-isopropyl ether to givethe title compound as its hydrochloric acid salt, m.p. l23l25.

The salt is dissolved in a minimum amount of water to which chloroformis added. While stirring, 10 percent aqueous sodium carbonate is addeduntil the solution becomes distinctly basic (pH 9l l The layers areseparated, the aqueous phase is extracted repeatedly with chloroform andthe combined extracts are washed with water, dried (MgSO andconcentrated to give the title compound.

The title compound is also prepared by heating a solution of2-n-butyl-3-[4-(2-hydroxy-3- chloro)propoxybenzoyl]benzofuran(chlorohydrin product) in ethanol with isopropylamine as describedabove.

EXAMPLE 2 2-n-Butyl-3-[ 3 ',5 -diiodo-4-( 2-hydroxy-3-tbutylamino)-propoxybenzoyl benzofuran A mixture of 10.8 g. (0.02 mol.) of2-n-butyl-3- (3 ,5 '-diiodo-4-hydroxybenzoyl )benzofuran, 1 g. (0.025mol.) of sodium hydroxide and 3 g. of epichlorohydrin in ml. of waterwas stirred at 25 for 12 hours. The reaction mixture was extracted withchloroform and the extracts were washed with water, dried (MgSO andconcentrated to give a mixture of2-nbutyl-3-[3',5'-diiodo-4'-(2,3-epoxy)propoxybenzoyl]- benzofuran and2-n-butyl-3-[3,5-diiodo-4-(2- hydroxy3-chloro)propoxybenzoyl]benzofuranwhich was separated by dry column chromatography on alumina withmethylene chloride.

A solution of l g. (0.0017 mol.) of 2-n-butyl-3-[3,5-diiodo-4-(2,3-epoxy)propoxybenzoyl]benzofuran and 10 ml. of t-butylaminein 50 ml. of ethanol was stirred at 25 for 24 hours. The solvent andexcess amine were removed in vacuo to give the title compound which wasconverted to its hydrochloric acid salt as described in Example 1.

EXAMPLE 3 2-Butyl-3-[4'-(2-hydroxy-3-piperidino)propoxybenzoyl]-benzofuran A solution of 2-n-butyl-3-[4-(2,3-epoxy)propoxybenzoyl]benzofuran and excess piperidine in ethanol wasrefluxed for 12 hours. Concentra' tion in vacuo gave the title compoundwhich was dissolved in ethanol and converted to its hydrochloric acidsalt by the procedure described in Example 1, m.p. l3 ll 33(ethanol-ether).

EXAMPLE 4 When pyrrolidine, morholine or 30 percent aqueous methyl aminewas substituted in the procedure of Example 3 for piperidine, there wasobtained 2-n-butyl-3-[4-(2-hydroxy-3-pyrrolidino)propoxybenzoyl1benzofuran,2-n-butyl-3-[4'-(2-hydroxy-3- morpholino)propoxybenzoyl]benzofuran and2-nbutyl-3-[4-(2-hydroxy-3-methylamino)propoxybenzoyll-benzofuran,respectively.

The substituted benzofurans prepared above were converted to theirhaxamic acid salts by addition of a 10 percent solution of hexamic acidin ethanol to a solution of the amine in ethanol.

EXAMPLE 2-n-Butyl-3[4'-(2-hydroxy-3tbutylamino)propoxybenzoyl]-benzofuran The title compound was preparedby substitution of t-butylamine in the procedure of Example 3 forpiperidine. The corresponding hydrochloric acid salt was preparedasdescribed in Example 1, mp. 122l23 (ethanol). 1

EXAMPLE 6 2-n-Butyl-3-[4'-(2-hydroxy-3-succinimido)propoxybenzoyll-benzofuran A mixture of 8.0 g. (0.024 mol.)of 2-n-butyl-3-[4'- (2,3-epoxy)propoxybenzoyllbenzofuran and 2.5 g.(0.025 mol.) of succinimide in 100 ml. of ethanol containing 1 ml. ofpyridine was refluxed with stirring for 22 hours. The reaction mixturewas cooled to ambient temperature, then refrigerated for 12 hours. Theprecipitate was collected by filtration, washed with ethanol and etherand dried to give the title compound, m.p. l27l30 (ethanol).

EXAMPLE 7 2-n-Butyl-3-[ 3 ',5 -dibromo-4'-( 2-hydroxy-3- isopropylamino)-propoxybenzoyl benzofuran To a solution of g. (0.051 mol.)of2-n-butyl-3-(4- hydroxybenzoyl)benzofuran in 150 ml. of 1:1 aceticacid-water was added dropwise a solution of 8.5 g. of bromine in ml. ofacetic acid. The reaction mixture was stirred at for 3 hours, then itwas filtered and the solid product was washed with water, aqueous sodiumbisulfite. 5 percent aqueous sodium bicarbonate and again with water.The crude product was chromatographed on alumina with 2:1chloroformmethanol as eluant to give 2-n-butyl-3-(3,5'-dibromo-4'-'hydroxybenzoyl)benzofuran.

A mixture of 7 g. (0.014 mol.) of 2-n-butyl-3-(3',5'-dibromo-4'-hydroxybenzoyl)benzo'furan, 1 g. (0.025 mol.) of sodiumhydroxide and 15 ml. of epichlorohydrin in 100 ml. of water was refluxedfor 1 hour. After cooling, chloroform was added to the reaction mixtureand the layers were separated. The organic phase was washed with water,dried (Na SO,) and concentrated to give a mixture of2-n-butyl-3-[3',5-dibromo-4'- (2,3-epoxy)propoxybenzoyl]benzofuran and2-n-butyl- 3-[ 3 ',5 '-dibromo-4-( 2-hydroxy- 3-chloro)propoxybenzoyllbenzofuran. The mixture was separated by dry columnchromatography on alumina with chloroform as eluant and the chlorohydrinwas converted to additional epoxy compound as described in Example 1.

2-Butyl-3-8 3,5'-dibromo-4'-(2,3- epoxy)propoxybenzoyl]benzofuran (3.0g., 0.006 mol.) was heated with 25 ml. of isopropylamine in a Parr bombat 80 for 2hours. After cooling, the reaction mixture was concentratedin vacuo and the residue was chromatographed on alumina with chloroformas eluant to give .the title compound m.p. ll21 13 (ether).

EXAMPLE 8 2-n-Butyl 3-[3'-bromo-'4-(2-hyclroxy-3- Yisopropylamino)propoxybenzoyllbenzofuran A mixtureof 10.0 g. (0.034mol.) of 2-n-butyl-3-(4" hydrox benzoyl)benzofuranand 6 .1 g. (0.034mol.) of

N-bromosuccinimide in 150 ml. of damp dimethylformamide was refluxed for12 hours. The reaction mixtrure was poured into water and extracted,with chloroform. The extracts were washed repeatedly with water, thendried (Na so and concentrated to give 2-n-butyl-3-(3'-bromo-4-hydroxybenzoyl)-benzofuran.

2-Butyl-3-( 3 '-bromo-4 '-hydroxybenzoyl)benzofuran was converted to2-n-butyl-3-[3-bromo-4'-(2,3- epoxy)propoxybenzoyl]b'enzofuran bytreatment with epichlorohydrin as described in the procedure of Example7. V

The epoxide (4 g., 0.009 mol.) was heated with 20 ml. of isopropylamineat for 2.5 hours as described in Examples 1 and 7 to give the titlecompound.

EXAMPLE 9 2-n-Butyl-3-[ 3 -me thyl-4'-( 2'-hydroxy-3- isopropylamino)propoxybenzoyl]benzofuran A solution of 11.5 g. (0.07 mol.) of3-methyl-4- methoxybenzoic acid and 10.7 g. (0.09 mol.) of thionylchloride in 60 ml. of methylene chloride was refluxed on a steam bathfor 2 hours. Concentration in vacuo and distillation of the residue gave3-methyl-4- methoxybenzoic acid chloride, m.p. 3639.

To a cooled, stirred solution of 10.8 g. (0.058 mol.) of3-methyl-4-methoxybenzoic acid chloride and 9.4 g. (0.054 mol.) of2-n-butylbenzofuran in 40 ml. of carbon disulfide was added dropwiseover a 20 minute interval 28.2 g. (0.108 mol.) of stannic chloride.After addition, the reaction mixture was warmed to ambient temperatureand stirred for 2 hours. The mixturewas then poured onto ml. ofice-water and stirred for 1 hour. The solvent was removed, the productextracted into chloroform and the extracts were washed with water, dried(Na SO and cncentrated in vacuo to give2-n-butyl-3-(3'-methyl-4'-methoxybenzoyl)- benzofuran.

2-n-Butyl-3-( 3 '-methyl-4 -methoxybenzoyl )benzofuran (17.5 g., 0.05mol.) was combined 50 g. of freshly distilled pyridine hydrochloride andthe mixture was refluxed 1 hour. The hot mixture was poured withstirring onto an ice-dilute hydrochloric acid mixture and theprecipitate was collected to give 2-n-butyl-3-(3'-methyl-4'-hydroxybenzoyl)benzofuran.

2-n-Butyl-3-[3-methyl-4'-(2,3-epoxy)propoxy)benzoyllbenzofuran wasprepared from 2-n-butyl-3-(3'- methyl-4'-hydroxybenzoyl)benzofuran andepichlorohydrin as described in Example 7.

Opening of the epoxy compound with isopropylamine to give the titlecompound was accomplished as described in Example 7.

EXAMPLE l0 2-n-Butyl-3-[3 ',5 '-dimethyl-4-(2-hydroxy-3- isopropylamino)-propoxybenzoyl]benzofuran To a cooled (ice bath) mixture of 9.4 g.(0.054 mol.) of 2-n-butylbenzofuran and 11.5 g. (0.058 mol.) of3,5-dimethyl-4-methoxybenzoic acid chloride in 100 ml. of methylenechloride was added dropwise 28.7 g. (0.11 mol.) of stannic chloride. Thereaction mixture was allowed to warm to ambient temperature, thenstirred for 2 hours. Water was slowly added to the mixture and it wasstirred an additional 30 minutes. The layers were separated and theorganic phase was washed with water until the washings were neutral,

' dimethyl-4-(2-hydroxy-3-isopropylamino)- dried (MgSO and concentratedto give 2-n-butyl-3- (3,5'-dimethyl-4'-methoxybenzoyl)benzofuran.

benzofuran was demethylated with pyridine hydrochloride as previouslydescribed to give 2-n-butyl-3-(3',5'-dimethyl-4'-hydroxybenzoyl)benzofuran which was treated withepichlorohydrin followed by isopropylamine as described in the procedureof Example 7 to ultimately give the title compound. 2-n-Butyl-3-[3',5-

propoxybenzoyl]benzofuran was converted to the correspondinghydrochloric acid salt as described in Example l, m.p. 202203(ethanol-ether).

EXAMPLE 1 1 2-n-Butyl-3-[3 '-chloro-4 2-hydroxy-3- isopropylamino)propoxybenzoyl ]benzofuran A solution of 25 g. (0.14 mol.) of3-chloro-4- hydroxybenzoic acid in 200 ml. of methanol containing 2 ml.of sulfuric acid was refluxed for 12 hours. After cooling, excessmethanol was evaporated, water was added to the residue and it was madebasic with 10 percent aqueous sodium hydroxide. The precipitate wascollected, washed with water and dried in vacuo to give3-chloro-4-hydroxybenzoic acid methyl ester, m.p. 105107C.

To a cooled solution of 14.5 g. (0.078 mol.) of3-chl0ro-4-hydroxybenzoic acid methyl ester and 4.0 g. (0.1 mol.) ofsodium hydroxide in 100 ml. of water was dropwise added 9.8 g. (7.3 ml.,0.079 mol.) of dimethyl sulfate. The reaction mixture was refluxed for 2hours. After cooling, ether was added and the layers were separated. Theorganic phase was washed with water, dilute sulfuric acid and water,dried (Na SO 4) and concentrated in vacuo to give3-chloro-4-methoxybenzoic acid methyl ester, m.p. 7274.

A mixture of 10.4 g. (0.052 mol.) of 3-chloro-4- methoxybenzoic acidmethyl ester and 3.5 g. (0.09 mol.) of sodium hydroxide in 150 ml. ofwater was refluxed for 2 hours. The reaction mixture was cooled andacidified with 10 percent aqueous hydrochloric acid to precipitate3-chloro-4-methoxybenzoic acid, m.p. l99202. The acid was refluxed withthionyl chloride as described in the procedure of Example 9 to give 3chloro-4-methoxybenzoic acid chloride, m.p. 55-57.

2-n-Butyl-3-(3'-chloro-4-methoxybenzoy1)benzofuran was prepared byacylation of Z-n-butylbenzofuran with 3-chloro-4-metoxybenzoic acidchloride as described in the procedure of Example 10. The subsequentsteps of demethylation, epoxide formation and ring opening of the2-n-butyl-3-[3'-chloro-4'-(2,3- epoxy)propoxybenzoyl]benzofuran to givethe title compound were accomplished as previously described.

Addition of an ethereal solution of oxalic acid to a solution of thetitle compound in ether gave the oxalic acid addition salt. The oxalatewas converted to the hydrochloric acid salt by passage of a solution of2-nisopropylamino)propoxybenzoyl]benzofuran oxalate in ethanol throughan Amberlite IRA-401 chloride ion exchange column.

EXAMPLE 12 2-n-Butyl-3-[ 3 ',5 '-dichloro-4 2-hydroxy-3- isopropylamino)-propoxybenzoyl benzofuran To a suspension of 56.6 g. of calciumhypochlorite in 225 m1. of warm water was added a solution of 39.6 g.

of potassium carbonate and 11.3 g. of potassium hydroxide in 120 ml. ofwater. The reaction vessel was stoppered and vigorously shaken until thegel which initially formed became fluid. The solid material was removedby filtration and the filtrate of aqueous potassium hypochlorite (45.3g., 0.35 mol.) was then added dropwise to a cooled (ice bath), stirredsolution of 38.3 g. (0.13 mol.) of2-n-butyl-3-(4'-hydroxybenzoyl)benzofuran in 200 ml. of methanol and 100ml. of 5 percent sodium hydroxide. After addition the reaction mixturewas refluxed for 5 minutes, then cooled and left to stand at 25 for 12hours. The mixture was acidified by addition of an ethereal solution ofhydrogen chloride, additional amounts of ether were added and the layerswere separated. The organic phase was washed with water, dried (Na SOand concentrated in vacuo to yield 2-n-butyl-3-(2,5-dichloro-4-hydroxybenzoyl)benzofuran, m.p. l l 14 (cyclohexane).

2-n-Butyl-3-(3',5'-dichloro-4-hydroxybenzoyl)- benzofuran was convertedto the corresponding (2,3- epoxy)-propoxybenzoylbenzofuran which wasring opened with isopropylamine as described in the procedure of Example7 to give the title compound. The hydrochloric acid salt was formed asdescribed in Exam ple 1, mp. 151-l53 (ethanol-ether).

EXAMPLE l3 2-n-Butyl-3-[2'-chloro-4-( 2-hydroxy-3- isopropylamino)-propoxybenzoyl benzofuran 2-Chloro-4-methoxybenzoic acid (6.2 g.,0.033 mol.) was converted to the corresponding acid chloride by heatingwith 75 ml. of thionyl chloride for 2 hours on a steam bath.

2-n-Butylbenzofuran (5.7 g., 0.033 mol.) was acyl ated with 6.7 g.(0.033 mol.) of 2-chloro-4- methoxybenzoic acid chloride in the presenceof 18 g. (0.07 mol.) of stannic chloride as described in the procedureof Example 10 to give 2-n-butyl-3-(2-chloro-4-methoxybenzoyl)benzofuran. The subsequent demethylation, epoxycompound formation and ring opening of the epoxide to give the titlecompound were carried out as previously described in Examples 9 andEXAMPLE 14 2-n-Butyl-3-[ 3 2-hydroxy-3-isopropylamino)propoxybenzoyl]-benzofuran EXAMPLE 15 2-n-Butyl-3-[22-hydroxy-3- isopropylamino )propoxybenzoyl]-benzofuran Acylation of 9.4g. (0.054 mol.) of 2-nbutylbenzofuran with 9.9 g. (0.058 mol.) ofo-anisoyl chloride according to the procedure described in Example 10gave 2-n-butyl-3-(2'-methoxybenzoyl)benzofuran which was demethylatedwith pyridine hydrochloride as previously described to give 2-n-butyl-3-(2'-hydroxybenzoyl)benzofuran.

A mixture of 7.5 g. (0.025 mol.) of 2-n-butyl-3-(2-hydroxybenzoyl)benzofuran, 25 ml. of epichlorohydrin and 15.0 g. ofpotassium carbonate in 150 ml. of ethanol was refluxed for 3 hours.After cooling the reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was dissolved in water and aqueoussolution was extracted with methylene chloride. The extracts werecombined, dried (Na SO and concentrated to give an oily residue that waschromatographed on alumina with chloroform as the eluant to give2-n-butyl-3-[2'-(2,3-epoxy)propoxybenzoyl]benzofuran.

The epoxy compound was heated with isopropylamine as described in theprocedure of Example 7 to give the title compound.

EXAMPLE l6 2-n-Butyl-3-[4 '-chloro-2 2-hydroxy-3- isopropylamino)-propoxybenzoy1]benzofuran Acylation of 13.1 g. (0.075 mol.) ofZ-n-butylbenzofuran with 15.4 g. (0.075 mol.) of 4-chloro-2-methoxybenzoic acid chloride, prepared from 4-chloro-2-methoxybenzoicacid and thionyl chloride as previously described, according to theprocedure of Example 10 gave 2-n-butyl-3-(4'-chloro-2-methoxybenzoyl)benzofuran. Demethylation as previously described gave2-n-butyl-3-(4'-chloro-2'- hydroxybenzoyl)benzofuran.

A mixture of 2-n-butyl-3-(4-chloro-2'-hydroxybenzoyl)benzofuran, 30 ml.of epichlorohydrin and g. of potassium carbonate in 200 ml. of ethanolwas refluxed for 18 hours. The reaction mixture was concentrated, waterwas added to the residue and the aqueous solution was extracted withmethylene chloride. The extracts were washed with water, dried (MgSO andconcentrated in vacuo to give 2-n-butyl-3-[4'-chloro-2'-(2,3-epoxy)propoxybenzoyl]-benzofuran which was purified by drycolumn chromatography on alumina with chloroform as eluant.

The epoxy compound was heated with isopropylamine as described in theprocedure of Example 7 to give the title compound.

EXAMPLE 17 To a solution of 30 g. (0.102 mol.) of 2-n-buty1-3-(4'-hydroxybenzoyl)benzofuran in 100 ml. of dioxane was added a solution of4.5 g. (0.11 mol.) of sodium hydroxide in 10 ml. of water followed by 50g. (0.552 mol.) of 3-chloro-2-methylpropene. The mixture was refluxedfor 12 hours, then cooled and poured into 450 ml. of water. The aqueousmixture was extracted with ether and the extracts were combined, dried(MgSO and concentrated in vacuo to give 2-n-butyl-3-[4'-(2-methylprop-El-ene)oxybenzoyl]benzofuran which was purified bychromatography on alumina with chloroform as eluant.

To a cooled (ice bath), stirred solution'of 10.4 g. (0.03 mol.) of thebenzofuran olefin in 25ml. of methylene chloride was added dropwise asolution of 7.52 g. (0.04 mol.) of m-chloroperbenzoic acid in 100 ml. ofmethylene chloride. The reaction mixture was allowed to warm to ambienttemperature, then it was stirred for 1 hour. An aqueous solution ofsodium sulfite was added to quench the reaction, the layers wereseparated and the organic layer was washed with 5 percent aqueous sodiumbicarbonate, dried (MgSO and concentrated in vacuo to yield2-n-butyl-3-[4-(2- methyl-2,3-epoxy)propoxybenzoyl]benzofuran.

The epoxy compound was heated with isopropylamine in ethanol asdescribed in the procedure of Example l to give2-n-butyl-3-[4'-(2-hydroxy-2-methyl-3-isopropylamino)-propoxybenzoyl]benzofuran.

By similar methods, substitution of an equivalent amount of3-chloro-l-methylpropene in the above procedure followed by thesynthetic steps of epoxidation and ring opening of the resultant epoxycompound with isopropylamine gives, ultimately, a mixture of2-nbutyl-3-[4 2-hydroxyl-methyl-3-isopropylamino)propoxybenzoyl]benzofuran and2-nbutyl-3-[4'-(2-hydroxy-3-methyl-3-isopropylamino)propoxybenzoyllbenzofuran, which is separated by drycolumn chromatography on alumina.

EXAMPLE l8 2-[4'-( 2-Hydroxy-3-isopropylamino )propoxybenzoyl]-benzofuran 2-[4'-(2,3-epoxy)propoxybenzoyl]benzofuran was prepared from12.0 g. (0.050 mol.) of 2-(4- hydroxyben'zoyl)-benzofuran, 3.0 g. ofsodium hydroxide and 30 ml. of epichlorohydrin as described in theprocedure of Example 7.

The epoxide ring was opened by heating with isopropylamine as describedin Example 7 to give the title compound, m.p. Preparation of thehydrochloric acid salt was accomplished as described in Example 1, m.p.158l60 (ethanol-ether).

EXAMPLE 19 2-[3 '-Chloro-4'-( 2-hydr0xy-3-isopropylamino)propoxybenzoyl]-benzofuran2-[3-Chloro-4'-(2,3-epoxy)propoxybenzoyl]benzofuran was prepared from2-(3'-chloro-4- hydroxybenzoyl)benzofuran and epichlorohydrin accordingto the procedure described in Example 7.

The epoxide was opened by heating with isopropylamine as described inExample 7 to give the title compound, m.p. 1 l71 19 (benzene-hexane).

EXAMPLE 20- 3-[4'-( 2-Hydroxy-3-isopropylamino)propoxybenzoyl1-benzofuran To a solution of the Grignard reagent prepared from 4.27 g.(0.14 g. -atom) of magnesium turnings and 31.0 g. (0.13 mol.) of4-iodoanisole in 50 ml. of ether was added dropwise a solution of 10.0g. (0.07 mol.) of 3- cyanobenzofuran in ml. of ether. The reactionmixture was stirred at 25 for 17 hours, then 30 ml. of water was addedfollowed by a mixture of 20 ml. of sulfuric acid and 40 ml. of water.Additional amounts of the acid solution were added to dissolve theprecipitate that formed in the reaction mixture. The mixture was pouredinto 500 ml. of water and the aqueous solution was extracted withchloroform. The extracts were dried (MgSO and concentrated in vacuo togive 3-(4'- methoxybenzoyl)benzofuran which was purified bychromatography on alumina with chloroform, m.p. 89-90 (hexane-benzene).

Demethylation with pyridine hydrochloride gave 3-(4'-hydroxybenzoyl)benzofuran which was reacted with epichlorohydrin aspreviously described in Example 7. The epoxide ring was opened withisopropylamine as described above to give the title compound which waspurified by dry column chromatography on alumina with chloroform. Theoxalic acid salt was prepared by the procedure of Example 1 l, m.p.198200 (ethanol).

EXAMPLE 21 2-Methyl-3-I 4-( 2-hydroxy-3-isopropylamino)propoxybenzoyl]-benzofuran 2-Methylbenzofuran (7.25 g.,0.055 mol.) was acylated with 15.7 g. (0.092 mol.) of anisoyl chlorideaccording to the procedure described in Example 10 to give2-methyl-3-(4'-methoxybenzoyl )benzofuran.

Demethylation, reaction of the 2-methyl-3-(.4- hydroxybenzoyl)benzofuranwith epichlorohydrin and subsequent epoxide ring opening withisopropylamine were accomplished as described in the procedures ofExamples 9 and 7 to give the title compound which was purified by drycolumn chromatography on alumina with chloroform as eluant.

EXAMPLE 22 2-Ethyl-3-(4'-hydroxybenzoyl)benzofuran was treated withepichlorohydrin according to the procedure of Example 7 to give2-ethy1-3-[4'-(2,3- epoxy)propoxybenzoyl]benzofurana which wassubsequently heated with isopropylamine as previously described to give2-ethyl-3-[4-(2-hydroxy-3- isopropylamino)propoxybenzoyl]benzofuran. Thepropanolamine was converted to the corresponding hydrochloric acid saltas described in Example 1, mp. 82-84 (ether-ethanol).

Similarly, 2-propyl-3-[4'-(2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran was prepared by treatment of2-propyl-3-(4'-hydroxybenzoy1)- benzofuran with epichlorohydrin followedby opening of the epoxide function with isopropylamine as described inthe procedure of Example 7.

EXAMPLE 23 Z-Phenylbenzofuran (7.81 g., 0.040 mol.) was acylated'with7.0 g.'(0.041 mol.) of anisoyl chloride according to the proceduredescribed in Example 10 to give2-phenyl-3-(4'-methoxybenzoyl)benzofuran.

Demethylation, reaction of the 2-ph3ny1-3-(4'- hydroxybenzoyl)benzofuranwith epichlorohydrin and subsequent epoxide ring opening withisopropylamine were accomplished as described in Examples 9 and 7 togive 2-phenyl-3-[4-(2-hydroxy-3-isopropylamine)propoxybenzoyllbenzofuran, m.p. 4350.

In like manner, 2-phenyl-3-[3 '-chloro 4'-(2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran was prepared by acylation of2-phenylbenzofuran with 3-chloro-4-methoxybenzoic acid chloride followedby the synthetic sequence of demethylation, reaction withepichlorohydrin and treatment of the 2-phenyl-3-[3'-chloro-4'-(2,3-epoxy)propoxybenzoyl[benzofuran formed withisopropylamine as previously described.

EXAMPLE 24 2-Benzyl-3- 4 2-hydroxy-3- isopropylamino)propoxybenzoyl]-benzofuran Acylation of 20.1 g. (0.096 mol.) of2-benzy1benzofuran with 17.5 g. (0.103 mol.) 'of anisoyl chlorideaccording to the procedure of Example 10 gave 2-benzyl-3-(4'-1nethoxybenzoy1)benzofuran which was demctliylated withpyridine hydrochloride to give 2- benzyl-3-(4-hydroxybenzoyl)benzofuran,m.p. 146-149. 4

Subsequent treatment of 2-benzyl-3-(4-hydroxybenzoyl )benzofuran withepichlorohydrin and ring opening of the epoxide thus formed withisopropylamine as previously described gave the title compound. m.p.1161 19 (ethanol).

EXAMPLE 25 '2-n-Butyl-3-[ 4'-( 2-hydroxy-3- benzylamino)propoxybenzoyll-benzofuran A mixture of 4.4 g. (0.015 mol.) of2-n-butyl-3-(4'- hydroxybenzoyl)benzofuran, 4.66 g. (0.034 mol.) ofepibromohydrin and 2.08 g. (0.015 mol.) of anhydrous potassium carbonatein 50 ml. of dry acetone was refluxed for 12 hours. The reaction mixturewas cooled. filtered and the filtrate was concentrated in vacuo anddistilled at reduced pressure to remove all traces of epibromohydrinfrom the product 2-n-buty1-3-[4-(2,3- epoxy)propoxybenzoyll-benzofuran.

A solution of 5.14 g. (0.014 mol.) of 2-n-butyl-3-[4-(2,3-epoxy)propoxybenzoy1lbenzofuran and 2.14 g. (0.02 mol.) ofbenzylamine in 60 ml. of ethanol was refluxed for 4 hours. Concentrationin vacuo gave the title compound which was converted to thecorresponding hydrochloric acid salt as described in the pro cedure ofExample 1, mp. l68-l70.

EXAMPLE 26 2-( 4'-Chlorobenzyl )-3-[4'-( 2-hydroxy-3- isopropylamino)propoxybenzoyl benzofuran To a solution of 15.3 g. (0.125 mol.) ofsalicylaldehyde in ml. of acetone was added 7.0 g. (0.125 mol.) ofpotassium hydroxide dissolved in a minimum amount of water.a-Bromo-p-chloroacetophenone (29.16 g., 0.125 mol.) was added dropwisewith stirring and cooling (ice bath). After addition, the reactionmixture was stirred at 25 for 12 hours. The precipitate was collected byfiltration, washed with water and combined with the residue remainingafter concentration of the filtrate to give 2-(4'-chlorobenzoyl)-3-hydroxycoumaran which was immediately dehydrated in the presence ofp-toluenesulfonic acid to yield 2(4- chlorobenzoyl)benzofuran.

Hydrazine hydrate (28.0 g., 0.5 mol.) was added to a solution of 42.0 g.(0.16 mol.) of 2-(4'-chlorobenzoyl)-benzofuran in 400 ml. of ethanol andthe reaction mixture was refluxed overnight. The solution wasconcentrated in vacuo, chloroform was added and the chloroform solutionwas washed with saturated aqueous sodium chloride, dried (MgSO andconcentrated to yield the corresponding hydrazone. The hydrazone wasdissolved in 100 ml. of dry dimethyl sulfoxide and added dropwise over a4 hour interval to a slurry of 36.4 g. (0.32 mol.) of potassiumt-butoxide in 100 m1. of dry dimethyl sulfoxide. The reaction mixturewas poured into 500 ml. of water and the aqueous solution was extractedwith chloroform. The extracts were washed with water, dried (MgSO,) andconcentrated in vacuo to give 2(4-chlorobenzyl)benzofuran which waspurified by chromatography on silica gel with carbon tetrachloride aseluant.

Acylation of 2-(4-chlorobenzyl)benzofuran with anisoyl chloride wasaccomplished as described in Example l0. Demethylation with pyridinehydrochloride as previously described followed by treatment of the 2(4'-chlorobenzyl )-3-( 4 '-hydroxybenzoyl )benzofuran with epibromohydrin asdescribed in the procedure of Example 25 and subsequent epoxide ringopening with isopropylamine according to the procedure of Example 7 gavethe title compound. The corresponding hydrotrifluoromethylacetophenonein 20 ml. of anhydrous ether was added with cooling and stirring 0.15 g.of anhydrous aluminum chloride and 20.2 g. (0.127 mol.) of 1 bromine.The reaction mixture was concentrated in vacuo and the residue wasdistilled to give a-bromo-mtrifluoromethylacetophenone, b.p. l35l40 (20mm.).

Substitution of an equivalent amount ofa-bromo-mtrifluoromethylacetophenone in the procedure of Example 26 fora-bromo-p-chloroacetophenone followed by treatment of the2-(3-trifluoromethylben zoyl)benzofuran with-hydrazine hydrateultimately gave 2-(3'- trifluoromethylbenzyl)benzofuran, b.p. 195-l97(25 mm.).

Acylation of 2-(3'-trifluoromethylbenzyl)benzofuran with anisoylchloride was carried out as outlined in the procedure of Example 10.Demethylation with pyridine hydrochloride, treatment withepichlorohydrin and subsequent epoxide ring opening with isopropylaminewere accomplished as described in the procedure of Examples 9 and 7 togive the title compound.

EXAMPLE 28 with pyridine hydrochloride as previously described,

2-(4-chlorophenyl)-3-(4'-hydroxybenzoyl)benzofuran was obtained.

Reaction of 2-(4'-chlorophenyl)-3-(4-hydroxybenzoyl)benzofuran withepichlorohydrin and subsequent ring opening with isopropylamineaccording to the procedure of Example 7 gave 2-(4'-chlorophenyl)-3-[4-(2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran.

Similarly, acylation of 2-(4'-tolyl)benzofuran with anisoyl chloride andsubsequent demethylation with pyridine hydrochloride gave2-(4-tolyl)-3-(4- hydroxybenzoyl)-benzofuran.

Treatment of 2-(4-tolyl)-3-(4-hydroxybenzoyl)- benzofuran withepichlorohydrin followed by ring opening of the epoxy compound withisopropylamine as described in the procedure of Example 7 gave 2-(4-tolyl)-3-[4-(2-hydroxy-3- isopropylamino)propoxybenzoyllbenzofuran whichwas converted to the corresponding hydrochloric acid salt as describedin Example 1, mp. 8087.

In like manner,. 5-bromo-2-(p-bromophenyl)benzofuran is acylated withanisoyl'chloride and the resulting5-bromo-2-(-4'bromophenyl)-3-(4'-methoxybenzoyl)benzofuran isdemethylated and the product treated with epichlorohydrin to give anepoxy compound which is subsequently opened with isopropyla mine to giveS-bromo-2-(4-bromophenyl)-3-[4'-(2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran.

EXAMPLE 29 2-n-Butyl-5-chloro-3-[4-(2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran A mixture of 27 g. (0.18 mol.)of 5- chlorobenzofuran, 28.5 g. (0.18 mol.) of butyric anhydride, 18 g.(0.20 mol.) of butyric acid and 5 g. (0.05 mol.) of phosphoric acid wasrefluxed for 4 hours then stirred at 25 for 12 hours. The reactionmixture was 0 basicified with 10 percent aqueous sodium hydroxide,

chloroform was addedto the mixture and the layers were separated. Theorganic phase was washed with water, dried (MgSO and concentrated invacuo to give 2-butyryl-5-chlorobenzofuran.

A mixture of 31.5 g.'(0.14 mol.) of 2-butyryl-5- chlorobenzofuran and35ml. of 98 percent hydrazine in ml. of diethylene glycol was warmed fora few minutes on a steam bath. Then 23.3 g. of potassium hydroxide wasadded and 'the reaction mixture was refluxed for 2 hours. After cooling,water was added to the mixture and the resulting aqueous solution wasextracted with benzene. The extract was washed with water 10 percentaqueous hydrochloric acid and water, dried (MgSO and concentrated invacuo to yield 2-n-butyl-5-chlorobenzofuran. b.p. 70-75 (l0l5 mm.).

2-n-Butyl-5-chlorobenzofuran (9.5 g., 0.046 mol.) was acrylated with 8g. (0.047 mol.) of anisoyl chloride as described in the procedure ofExample 10 to give 2- n-butyl-5-chloro-3-(4'-niethoxybenzoyl)benzofuran.Demethylation followed 'by reaction of the 2-n-butyl-5-chloro-3-(4'-hydroxybenzoyl)benzofuran with epichlorohydrin andsubsequent opening of the epoxy compound formed with isopropylamine wascarried out as described in the procedures of Examples 9 and 7 to givethe title compound.

EXAMPLE 30 5-Chloro-2-phenyl-3-[4-( 2-hydroxy-3- isopropylamino)propoxybenzoyl]benzofuran A mixture of 14.2 g. (0.09 mol.) of cuprousphenylacetylide and 16.0 g. (0.08 mol.) of 2-bromo-4- chlorphenol in ml.of pyridine was refluxed under a nitrogen atmosphere for 18 hours. Thereaction mix ture was cooled and poured into 600 ml. of water. Theresulting precipitate was collected by filtration, washed with copiousamounts of water and continuously extracted with ethanol for 12 hours.Removal of the ethanol in vacuo gave a residue which was chromatographedon an alumina dr'y column with hexane to give5-chloro-Z-phenylbenzofuran, m.p. l40l43 (methanol).

Acylation of 5-chloro-2-phenylbenzofuran with anisoyl chloride wasaccomplished as described in the procedure of Example 10 to give5-chloro-2-phenyl-3-(4'- methoxybenzoyl)benzofuran which was thendemethylated and the product treated with epichlorohydrin as describedabove. Opening of the epoxide ring with isopropylamine as previouslydescribed gave the title compound.

EXAMPLE 31 A solution of 7.0 g. (0.017 mol.) of 2-n-butyl-3-[4- v(2-hydroxy-3-isopropylamino)propoxybenzoyl]benchloroform. The extractswere washed with percent aqueous sodium bicarbonate and water, dried(MgSO,) and concentrated in vacuo to give a mixture of2-nbutyl-3-[4'-(2-acetoxy-3-N-acetylisopropylamino)-propoxybenzoyl]benzofuran, 2-n-butyl-3-[4-(2-acetoxy-3-isopropylamino)propoxybenzoyl]benzofuran and2-n-butyl-3-[4-(2-hydroxy-3-N-acetylisopropylamino)propoxybenzoyl]-benzofuran which was separated bydry column chromatography on alumina with chloroform as eluant.

Alternatively, 2-n-butyl-3-[4'-(2-hydroxy-3-N-acetylisopropylamino)propoxybenzoyl]benzofuran was prepared by refluxing4.9 g. (0.01 mol.) of 2-nbutyl-3-[4'-(2-acetoxy-3-N-acetylisopropylamino)propoxybenzoyl]benzofuran with 5 ml. of percentaqueous sodium hydroxide in ml. of water for 1 hour. After cooling,chloroform was added to the reaction mixture, the layers were separatedand the organic phase was washed with water, dried (Na- 50 andconcentrated in vacuo to give the desired product.

In like manner, the (2-acetoxy-3-N-acetylamino)-(2-acetoxy-3-alkylamino)- and (2-hydroxy-3-N- acetylamino)-derivatives ofthe other (2-hydroxy-3- alkylamino)- benzofurans disclosed herein may beobtained.

EXAMPLE 3 2 n-butyrylamino)-, (Z-n-butyryloxy-3-alkylamino)- and(2-hyroxy-3-N-n-butyrylamino)-derivatives of the other(2-hydroxy-3-alkylamino)- benzofurans disclosed herein may be obtained.

EXAMPLE 3 3 2-n-Butyl-3-[4'-( 2-acetoxy-3-piperidino)propoxybenzoyll-benzofuran Substitution of an equivalent amount of2-n-butyl-3- [4'-(2-hydroxy-3-piperidino)propoxybenzoyHbenzofuran in theprocedure of Example 31 for 2-n-butyl-3-[4-(2-hydroxy-3-isopropylamino)propoxybenzoyllbenzofuran gives the titlecompound.

Likewise, substitution of the other (2-hydroxy-3- dialkylamino)-,(2-hydroxy-3-pyrrolidino)- or (2-hydroxy-3-morpholino)- benzofuransdisclosed above gives the corresponding(2-acetoxy-3-substitutedamino)-benzofurans.

EXAMPLE 34 Substitution of the following benzofurans: 3-(3',5-dibromo-4'-hydroxybenzoyl)-2- ethylbenzofuran3-ethyl-2-(4-hydroxybenzoyl)benzofuran2-(3'-chloro-4-hydroxybenzoyl)benzofuran 2-( 3 -fluoro-4'-hydroxybenzoyl)benzofuran 2-(2'-hydroxy-5-methylbenzoyl)benzofuran3-(3,5-diiodo-4'-hydroxybenzoyl)-2- ethylbenzofuran2-(2-hydroxybenzoyl)benzofuran in the procedure of Example 7 for2-n-bu'tyl-3-(4- hydroxybenzoyl)benzofuran with subsequent opening ofthe intermediate epoxy compound with isopropylamine as described inExample 7 gives, respectively:

3-[3',5-dibromo-4-(2-hydroxy-3-isopropylamino)-propoxybenzoyl]-2-ethylbenzofuran 3-ethyl-2-[4-(2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran 2-[3'-chloro-4-(2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran 2-[3'-fluoro-4'-(2-hydroxy-3-isopropylamino)propoxybenzoyl)benzofuran 2-[5'-methyl-2'-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran3-[3,5-diiodo-4'-(2-hydroxy-3-isopropylamino)-propoxybenzoyl]-2-ethylbenzofuran2-[2'-(2-hydroxy-3-isopropylamino)propoxybenzoyl]-benzofuran EXAMPLE 35Substitution of an equivalent amount of 2- (chloromethyl)butene in theprocedure of Example 17 for 3-chloro-2-methylpropene followed bytreatment of the product with m-chloroperbenzoic acid and subsequentopening of the epoxy compound formed with isopropylamine as described inExamples 17 and 7 gives 2-n-butyl-3-[4'-(2-ethyl-2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran.

In like manner, when an equivalent amount of 3- chloro-l-pentene issubstituted in the procedure of Example 17 for 3-chloro-2-methylpropeneand the product is treated with m-chloroperbenzoic acid and subsequentlyheated with isopropylamine as described above, there is prepared amixture of 2-n-butyl-3-[4'-l-ethyl-2-hydroxy-3-isopropylamino)propoxyben zoyl]benzofuran and2-n-butyl-3-[ 4 3-ethyl-2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran which is separated bychromatography on aluminia EXAMPLE 36 When an equivalent amount ofdiethyl amine is substituted in the procedure of Examples 1 or 3 forisopropylamine or piperidine, 2-n-butyl-3-[4'-(Z-hydroxy-3-diethylamino)propoxybenzoyl]benzofuran is obtained.

In a similar manner, reaction of 2-n-butyl-3-[4'-(2,3-epoxy)propoxybenzoyl]benzofuran with di-nbutylamine gives2-n-butyl-3-[4'-(2-hydroxy-3-di-nbutylamino )propoxybenzoyl ]benzofuran.

Likewise, substitution of N-ethyl-N-methylamine in the procedure ofExample 1 or Example 3 for isopropylamine or piperidine gives2-n-butyl-3-[4-(2- hydroxy-3-N-ethyl-N-methylamino)propoxybenzoyl]-benzofuran.

EXAMPLE 37 Substitution of an equivalent amount of a benzofuran listedbelow:

S-bromobenzofuran 6-chlorobenzofuran 7-chlorobenzofuran4-methylbenzofuran S-methylbenzofuran S-ethylbenzofuran in the procedureof Example 29 for chlorobenzofuran followed by the synthetic steps ofhydrazine reduction, acylation, demethylation, epoxide formation andopening of the epoxide with isopropylamine as described therein gives,ultimately, the following substituted benzofurans:

5-bromo-2-n-butyl-3-[4-(2-hydroxy-3-isopropylamino)-propoxybenzoyllbenzofuran2-n-butyl-6-chloro-3-[4'-(2-hydroxy-3-isopropylamino)propoxybenzoyllbenzofuran2-n-butyl-7-chloro-3-[4-(2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran2-n-butyl-3-[4-(2-hydroxy-3-isopropylamino)-propoxybenzoyl]-4-methylbenzofuran2-n-butyl-3-[4-(2-hydroxy-3-isopropylamino)-propoxybenzoyl]-5-methylbenzofuran 2-n-butyl-5-ethyl-3-[4'(2-hydroxy-3-isopropylamino)-propoxybenzoyl]benzofuran.

EXAMPLE 38 When an equivalent amount ethylbenzofuran is substituted inthe procedure of Example for 2-n-butylbenzofuran and the product isdemethylated with pyridine hydrochloride, followed by treatment of thehydroxyphenyl benzofuranyl ketone with epichlorohydrin and subsequentring opening of the resulting epoxy compound with isopropylamine aspreviously described, there is obtained 5-chloro-2-ethyl-3-[4-(2-hydroxy-3-isopropylamino)propoxybenzoyl]-benzofuran.

In like manner, 3-[4'-(2-hydroxy-3-isopropylamino)-propoxybenzoyl]-2-phenyl-7-trifluoromethylbenzofuran is obtained fromsubstitution of an equivalent amount of2-phenyl-7-trifluoromethylbenzofuran in the procedure of Example 10 for2-n-butylbenzofuran followed by the subsequent synthetic steps ofdemethylation, treatment withv epichlorohydrin and heating the epoxycompound thus formed with isopropylamine.

EXAMPLE 39 2-n-Butyl-3-[ '-methoxy-4-( 2-hydroxy-3- isopropylamine)-propoxybenzoyl]benzofuran A mixture of 17.4 g. (0.1 mol.) ofZ-n-butylbenzofuran and 19.1 g. (0.1 mol.) of 4-acetoxy-3-methoxybenzonitrile in 20 ml. of trifluoroacetic acid is refluxed for 3hours. The reaction mixture is cooled, diluted with 200 ml. of water andthe resulting aqueous solution is extracted with ether. The extracts-areconcentrated to dryness and the residue is dissolved in 100 ml. ofethanol and heated with 20 ml. of 10 percent aqueous sodium carbonatefor 2 hours. The mixture is concentrated, the residue extracted withether and the extracts are dried and concentrated in vacuo to give 2-n-butyl-3-(3-methoxy-4-hydroxybenzoyl)- benzofuran.

2-n-Butyl-3-(3-methoxy-4-hydroxybenzoyl)benzofuran is treated withepichlorohydrin and the resulof 5-chloro-2- tant epoxy compound isheated with isopropylamine as previously described to give the titlecompound.

EXAMPLE 40 2-( 4'-Aminobenzyl)-3-[4'-( 2-hydroxy-3- isopropylamino)-propoxybenzoyl benzofuran Substitution of an equivalent amount ofa-bromo-pnitroacetophenone in the procedure of Example 26 fora-bromo-p-chloroacetophenone gives 2-(4'-nitrobenzoyl)benzofuran.

Sodium borohydride (7.4 g., 0.2 mol.) is added portionwise to a rapidlystirred solution of 26.7 g. (0.1 mol.) of 2-(4-nitrobenzoyl)benzofuranin methanol. The reaction mixture is stirred at 25 for 1 hour thenquenched by addition of water. The aqueous slurry is extracted withchloroform, the extracts are dried (MgSO and the solvent is removed invacuo to give 2-(a-hydroxy-4-nitrobenzyl)benzofuran which is immediatelyconverted to the corresponding oz-chloride by reaction with 14.3 g.(0.12 mol.) of thionyl chloride.

A mixture of 13.6 added. g. (0.36 mol.) of sodium borohydride and 14.4g. (0.05 mol.) of 2-(a-ch1oro-4- nitrobenzyl)benzofuran in 200 ml. of 80percent aqueous diglyme is stirred at 50 for 4 hours. The reactionmixture is then cooled and hexane followed by 4.0 g. (0.1 mol.) ofsodium hydroxide are addedd The layers are separated and the organicphase is dried (MgSO and concentrated to give2-(4-nitrobenzyl)benzofuran.

2-(4'-Nitrobenzyl)benzofuran is acylated with anisoyl chloride asdescribed in Example 10. Demethylation with pyridine hydrochloride aspreviously described gives3-(4-hydroxybenzoyl)-2-(4'-nitrobenzyl)benzofuran.

3-(4'-Hydroxybenzoyl)-2-(4-nitrobenzyl)benzofuran (37.3 g., 0.1 mol.) isadded in small portions to 56.45 g. (0.25 mol.) of stannous chloridedihydrate in ml. of concentrated hydrochloric acid. The reaction mixtureis heated at 50 for 3 hours, then stirred at 25 for 12 hours. Cooling(ice bath) enhances precipitation of the product salt which is collectedby filtration and dissolved in water. The aqueous solution is made basicby addition of 10 percent aqueous sodium hydroxide and extracted withchloroform. The extracts are dried (MgSO and concentrated to give 2-(4'-aminobenzyl)-3-(4'-hydroxybenzoyl)benzofuran.

Reaction of 2-(4'-aminobenzyl)-3-(4'-hydroxybenzoyl)benzofuran withepichlorohydrin followed by subsequent opening of the epoxy compoundthus formed with isopropylamine as previously described gives the titlecompound.

EXAMPLE 41 2-(4'-N,N-Dimethylaminobenzyl)-3-[4 2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran A mixture of2-(4-aminobenzyl)-3-(4'-hydroxybenzoyl)benzofuran (34.3 g., 0.1 mol.),35.5 g. (0.25 mol.) of methyl iodide and 31.8 g. (0.3 mol.) of sodiumcarbonate in 250 ml. of water is refluxed for 3 hours then cooled to 25and extracted with chloroform. The extracts are dried (MgSO andconcentrated in vacuo to give 2-(4'-N,N-dimethylaminobenzyl)-3(4'hydroxybenzoyl)benzofuran.

Treatment of 2-(4-N,N-dimethylaminobenzyl)-3-(4-hydroxybenzoyl)benzofuran with epichlorohydrin with subsequentopening of the epoxy compound thus formed with isopropylamine by methodsoutlined above gives the title compound.

EXAMPLE 42 2-( 3 '-Anilino )-3-[4 2-hydroxy-3- isopropylamino)propoxybenzoyl]benzofuran A solution of g. (0. 105 mol.) of cuprousiodide in 400 ml. of ammonium hydroxide is poured with stirring into asolution of 15.4 g. (0.105 mol.) of m-nitrophenylacetylene in 500 ml. ofethanol. The reaction mixture is leftto stand at for minutes then it isfiltered and the product washed five times each with water, ethanol andether to give cuprous m-nitrophenylacetylide.

A mixture of 5.3 g. (0.024 mol.) of o-iodophenol and 5.0 g. (0.024 mol.)of cuprous m-nitrophenylacetylide in 100 ml. of pyridine is refluxed for7 hours under a nitrogen atmosphere. The reaction mixture is poured intowater, the aqueous slurry filtered and the filtrate is extracted withmethylene chloride. The extracts are washed with water, dried (MgSO andconcentrated to give 2-m-nitrophenylbenzofuran.

Acylation of 2-m-nitrophenylbenzofuran with anisoyl I chloride isaccomplished as described in the procedure of Example 10. Demethylationwith pyridine hydrochloride as previously described gives 3-(4-hydroxybenzoyl )-2-( 3 -nitrophenyl)benzofuran.

2-(3'-Aminophenyl)-3-(4'-hydroxybenzoyl)benzofuran is prepared byreduction of 3-(4-hydroxybenzoyl)- 2-(3-nitrophenyl)benzofuran accordingto the procedure of Example 40. Reaction of thiscompound withepichlorohydrin followed by ring opening of the resultant epoxy compoundwith isopropylamine as previously described gives the title compoundEXAMPLE 43 2-( 3 -N-Ethylanilino )-3-[4'-( 2-hydroxy-3- isopropylamino)-propoxybenzoyl]benzofuran Substitution of 32.9 g. (0.1 mol.) of2-(3-anilino)-3- (4-hydroxybenzoyl)benzofuran and 15.6 g. (0.1 mol.) ofethyl iodide in the procedure of Example 41 for 2-(4'-aminobenzyl)-3-(4-hydroxybenzoyl)benzofuran and methyl iodide,respectively, gives 2-(3'-N-ethylanilino)-3-(4'-hydroxybenzoyl)benzofuran.

Treatment of 2-(3-N-ethylanilino)-3-(4'- hydroxybenzoyl)benzofuran withepichlorohydrin followed by opening of the resultant epoxy compound withisopropylamine according to methods described above gives the titlecompound.

EXAMPLE 44 When equivalent amounts of ohydroxyacetophenone oro-hydroxybenzophenone are substituted in the procedure of Example 26 forsalicyladehyde and a-bromo-p-methoxyacetophenone is sub stituted fora-bromo-p-chloroacetophenone, there are ultimately obtained3-methyl-2-(4-methoxybenzoyl)- benzofuran and3-phenyl-2-(4-methoxybenzoyl)benzofuran.

Demethylation of 3-methyl-2-(4-methoxybenzoyl)- benzofuran with pyridinehydrochloride as previously described followed by treatment of the3-methyl-2-(4- hydroxybenzoyl)benzofuran with epichlorohydrin andsubsequent opening of the intermediate epoxy compound withisopropylamine as described herein gives2-[4-(2-hydroxy-3-isopropylamino)propoxybenzoyl]- 3-methylbenzofuran. 7

Similarly, 3-phenyl-2-(4-methoxybenz0yl)benzofuran is demethylated andthe resultant 2-(4'- hydroxybenzoyl)-3-phenylbenzofuran is reacted withepichlorohydrin followed by ring opening of the epoxy compound thusformed with isopropylamine to give 2- [4-(2hydroxy-3-isopropylamino)-propoxybenzoyl]-3 phenylbenzofuran.

EXAMPLE 45 Acylation of S-t-butoxy-2-ethylbenzofuran with anisoylchloride according to the procedure of Example 10 with subsequentdemethylation, reaction with epichlorohydrin and opening of theresulting epoxy compound with isopropylamine gives5-t-butoxy-2-ethyl-3-[4'-(2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran.

Similarly, Z-(p-ethoxybenzyl)benzofuran is acylated and the2-(4'-ethoxybenzyl)-3-(4-methoxybenzoyl)- benzofuran is demethylated,the product treated with epichlorohydrin and the resultant epoxycompound opened with isopropylamine to give 2-(4-ethoxybenzyl)-3-[4-(2-hydroxy-3-isopropylamino)propoxybenzoyl]benzofuran.

' EXAMPLE 46 When an equivalent amount of 4- methoxybenzofuran orS-methoxybenzofuran is substituted in the procedure of Example 29 for 5-chlorobenzofuran there are prepared 2-n-butyl-4- methoxybenzofuran and2-n-butyl-5- methoxybenzofuran.

Reaction of 2-n-butyl-4- and S-methoxybenzofuran with4-acetoxybenzonitrile and hydrolysis of the prod ucts with aqueoussodium carbonate as described in the procedure of Example 39, followedby reaction of the 2-n-butyl-3-(4'-hydroxybenzoyl)-4- and 5-methoxybenzofurans thus formed with epichlorohydrin and subsequentepoxide ring -isopropylamino)propoxybenzoyl1with isopropylamine aspreviously described gives, respectively, 2-n-butyl-3-[4'-(2-hydroxy-3-isopropylamino )propoxybenzoyl) ]-4- methoxybenzofuran and2-n-butyl-3-[4'-(2-hydroxy-3- isopropylamine)propoxybenzoyl]-5-methoxybenzofuran.

What is claimed is:

l. A compound of the formula:

or a pharmaceutically acceptable acid addition salt thereof, in which:

R is hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl;

R is hydrogen, lower alkyl or phenyl(CH where n is 0 or 1 and the phenylmoiety is optionally substituted with lower alkyl, lower alkoxy,trifluoromethyl, halogen, NH NH(lower alkyl) or N(lower alkyl) R ishydrogen, halogen, lower alkyl or lower alkoxy;

m is l or 2;

R R and R are hydrogen or one of R,-, and R is methyl or ethyl;

R is hydrogen or lower alkanoyl; and

R is NH(lower alkyl), N(lower alkyl) NH(benzyl),

N(lower alkanoyl)(lower alkyl), piperidino, pyrrolidino, morpholino orsuccinimido.

2. A compound of claim 1 in which R is hydrogen. lower alkyl orphenyl(CH where n is or 1 and the phenyl moiety is optionallysubstituted with methyl, methoxy, trifluoromethyl or chloro, R R and Rare hydrogen, R is hydrogen or methyl and R is NH(isopropyl) orNH(t-butyl).

3. A compound of claim 2 in which R, is hydrogen or chloro in the5-position, R is hydrogen or halogen, m is l and R is hydrogen 4. Acompound of claim 3 in which R is hydrogen,

0H R is --El or -C isopropylamino )propoxybenzoyl ]benzofuran.

' Patent NO. 5, 9 Dated April 9, 975

Inventor(s) David To Hill and Bernard Loev It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

Column '7, lines 9-14, the formula should read:

. O O-CH -C-CH R -Lb R6 Column 9, line 55, "2Butyl38" should read2-g-Butyl-3-[ 0 Column 10, line 7, "2-Butyl-" should read Z-n-Butyl-Column 10, line 42, after "combined" insert with Column 12, line 17,"(2',5' should read (3',5'

G Column 15, line 21, "benzofurana" should read benzofuran Column 15,line 41, "2-ph3nyl" should read Z-phenyl- Column 15, line 55,"benzoyl[benzofuran" should read benzoyljbenzofuran Column 20, line 26,"2'-hydroxy-" should read 2'-(2hydroxy- Column 22, line 38, "56.45 g."should read 56.4 g.

Column 24, lines 38-39, delete "--isopropylamino)propoxybenzoylj andinsert opening Column 25, line 13, "one of R should read one of R RSigned and Sealed this v fourteenth D3) Of October 1975 [SEAL] Attest:

RUTH C. MASON c. MARSHALL DANN Arresting Officer Commissioner of Patentsand Trademarks

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1 in which R2 ishydrogen, lower alkyl or phenyl(CH2)n where n is 0 or 1 and the phenylmoiety is optionally substituted with methyl, methoxy, trifluoromethylor chloro, R5, R7 and R8 are hydrogen, R6 is hydrogen or methyl and R9is NH(isopropyl) or NH(t-butyl).
 3. A compound of claim 2 in which R1 ishydrogen or chloro in the 5-position, R4 is hydrogen or halogen, m is 1and R6 is hydrogen.
 4. A compound of claim 3 in which R1 is hydrogen, R3is
 5. A compound of claim 4 being the compound2-n-butyl-3-(4''-(2-hydroxy-3-isopropylamino)propoxybenzoyl)-benzofuran.6. A compound of claim 4 being the compound2-n-butyl-3-(3''-chloro-4''-(2-hydroxy-3-isopropylamino)propoxybenzoyl)benzofuran.
 7. A compound of claim 4being the compound 2-n-butyl-3-(4''-chloro-2''-(2-hydroxy-3-isopropylamino)propoxybenzoyl)benzofuran.
 8. A compound of claim 4being the compound 2-(4''-chlorobenzyl)-3-(4''-(2-hydroxy-3-isopropylamino)propoxybenzoyl)benzofuran.